This is an application for a K23 Mentored Patient-Oriented Research Career Development Award titled "Basal ganglia modulation of cognitive systems in Parkinson's disease". The primary goal of the proposed research is to investigate regional and brain network abnormalities associated with mild cognitive impairment (MCI) in Parkinson's disease (PD) patients using event-related and resting state functional MRI (fMRI). The rigorous education and training plan will increase the candidate's expertise in fMRI methodology, statistical analysis, behavioral neuroscience, and clinical research methods, thus providing the candidate the necessary skills to ensure success of the proposed research and to become an independent investigator. The candidate's long term career goal is to use fMRI to elucidate the pathophysiology of cognitive dysfunction in PD and to develop an fMRI based imaging tool that is a sensitive marker of cognitive impairment in PD and an objective biomarker of treatment response. This proposal investigates in vivo functional changes associated with cognitive dysfunction in early PD patients without (PD-noMCI) and with (PD-MCI) mild cognitive impairment, compared to normal controls. Aim 1 uses fMRI tasks targeting executive control processes that require activation of basal ganglia nuclei in normal controls to determine changes in basal ganglia and cortical activation associated with PD cognitive impairment. In addition to changes in regional brain activation, cognitive impairment in PD likely also stems from alterations in connectivity between critical brain regions;therefore in Aim 2 we will investigate functional connectivity between basal ganglia nuclei and the cortex using resting state fMRI. Finally, dopaminergic medications can lead to both cognitive enhancement and further impairment, depending on the cognitive function. Therefore, Aim 3 will investigate changes in basal ganglia and cortical activation, striato- cortical connectivity, and intrinsic networks in the PD-noMCI and PD-MCI groups while ON medications compared to the previously performed OFF medication studies. Changes in basal ganglia activation and functional connectivity associated with PD-MCI identified in this proposed research will help clarify the role of basal ganglia nuclei in early PD cognitive impairment and, thus, have implications on the development of therapies for this currently untreatable symptom. PUBLIC HEALTH RELEVANCE: Cognitive dysfunction in PD patients causes substantial human and financial costs and constitutes a growing public health challenge for the aging American population. The proposed research seeks to clarify the function of the basal ganglia in modulation of PD-associated cognitive impairment, ultimately promoting better treatments for PD patients.